WO2008020332A2 - Procédé de préparation de tartrate de (r)-tolterodine - Google Patents

Procédé de préparation de tartrate de (r)-tolterodine Download PDF

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Publication number
WO2008020332A2
WO2008020332A2 PCT/IB2007/003377 IB2007003377W WO2008020332A2 WO 2008020332 A2 WO2008020332 A2 WO 2008020332A2 IB 2007003377 W IB2007003377 W IB 2007003377W WO 2008020332 A2 WO2008020332 A2 WO 2008020332A2
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WO
WIPO (PCT)
Prior art keywords
formula
tolterodine
dialcohol
tartrate
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2007/003377
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English (en)
Spanish (es)
Other versions
WO2008020332A3 (fr
Inventor
Patricia FLORES SÁNCHEZ
Salvador Adrián AVILA QUEVEDO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Uquifa Mexico SA de CV
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Uquifa Mexico SA de CV
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Publication date
Application filed by Uquifa Mexico SA de CV filed Critical Uquifa Mexico SA de CV
Publication of WO2008020332A2 publication Critical patent/WO2008020332A2/fr
Publication of WO2008020332A3 publication Critical patent/WO2008020332A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part

Definitions

  • the present invention relates to a synthesis process for obtaining tolterodine tartrate, a compound that is used as an active ingredient in the treatment of urinary incontinence.
  • Tolterodine belongs to a class of medications called antimuscarinics, which are used in the treatment of urinary conditions. Tolterodine is used in the treatment of urinary incontinence because it acts by preventing the contraction of the bladder and is commercially known as Detrusitol or Detrol LA.
  • the chemical name of the base tolterodine is N, N-düsopropyl-3- (2- hydroxy-5-methylphenyl) -3-phenylpropanamine. Taking into account that in the structure of the tolterodine a stereogenic center is present, biological activity studies have been carried out that have shown that the active enantiomer is that of the R configuration.
  • the tolterodine is an amine Stable salts are preferred for pharmaceutical use, so it is used as the (+) -tartaric acid salt, that is, as (R) -tolterodine tartrate (Scheme I):
  • the present invention describes an improved process for the preparation of tolterodine tartrate, with high yields and at a lower cost, thus being able to avoid the problems present in the prior art.
  • the tartrate preparation procedure Tolterodine of the present invention consists of four steps (Scheme V):
  • the benzopiranone (1) is subjected to a fairly simple reduction reaction, using sodium borohydride, methanol and toluene at a temperature between 5 and 15 0 C, preferably at 10 0 C 1 to obtain the dialcohol (12), with high performance Then, the two hydroxyl functions dialcohol (12) are protected using 2.0 to 3.0 equivalents of mesyl chloride, preferably 2.3 equivalents, in methylene chloride at a temperature between 10 and 20 0 C, preferably at 15 0 C, to yield compound dimesylated (13).
  • the previous step has the advantage that mesyl chloride serves to introduce a good leaving group that is necessary for the substitution reaction with diisopropylamine (14), which will give rise to tolterodine.
  • Other advantages are that the same reagent serves to protect the phenolic hydroxyl and that subsequent deprotection is easily carried out under basic conditions.
  • the dimesilado compound (13) is first treated with düsopropilamina in acetonitrile by heating between 80 and 1 1 O 0 C, preferably at 100 0 C, under a pressure of 2 to 2.5 bar, preferably 2.3 bar. Then, it is treated with sodium hydroxide in methanol at reflux to release the phenolic hydroxyl and, finally, the treatment of the reaction crude in ethyl acetate or methylene chloride, preferably ethyl acetate, with hydrobromic acid, allows easy isolation of the tolterodine in the form of the hydrobromide
  • tolterodine tartrate is obtained by treating the brornhydrate with sodium hydroxide to release the base and subsequently with (+) - tartaric acid to form the tartrate by means of fractional crystallization.
  • the benzopyranone of formula 1, the starting material of the process of the present invention, is a known compound and can be prepared in a simple manner according to the procedure described in the Australian Journal of Chemistry, 26, 899-906 (1973), or in example 1 of US 5,922,914.
  • the reaction mixture is heated at reflux for 2 to 4 hours.
  • the methanol is distilled under reduced pressure until the separation of two phases is observed; The upper one contains the product.
  • the lower phase is cooled to 5 to 1 0 0 C, 100 ml of cold water is added and washed with 50 ml of ethyl acetate.
  • To the organic phase 100 ml of ethyl acetate are added and washed twice with 75 ml of water.
  • the organic phases are combined and 10.8 ml of hydrobromic acid are added.
  • the suspension is cooled to 0 0 C and is thus maintained for 1.5 hours.
  • the solid is filtered and washed with ethyl acetate. After drying with reduced pressure at 60 0 C, 36.2 g of compound (14) obtained in a yield of 71%.
  • the tolterodine base obtained from 148 mmol of the hydrobromide (14), as indicated in Example 4, is dissolved in 600 ml of acetone at 48-50 ° C.
  • To this solution is added 33.30 g (222 mmol, 1.5 eq) of tartaric acid dissolved in 60 ml of hot MeOH, by means of an addition funnel for 30 minutes.
  • the suspension is heated at reflux for 1 hour. Subsequently, it is gradually cooled to 0 0 C and maintained at that temperature for 1 hour.
  • the solid formed was filtered and washed 2 times with 60 ml of a cold mixture of acetone / MeOH 90: 10. the compound obtained under vacuum at 60 D C overnight dried.
  • the product obtained (39.5 g) and 395 ml of MeOH are heated at reflux for 30 minutes.
  • the mixture is distilled to half the volume and 1120 ml of acetone is added in 30 minutes. It is heated at reflux for 1 hour and then gradually cooled to 0 0 C. It is filtered and washed twice with 40 ml of a cold mixture of acetone / MeOH 90: 10.
  • the product is dried under reduced pressure for 1 night. and recrystallizes once again in the same way. 26 g of the title compound are obtained in a yield of 39%.
  • the product has the same physical properties as that obtained according to the procedure of Example 4.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un procédé de préparation de tartrate de (R)-tolterodine qui comprend la réduction d'une benzopyranone de formule 1 avec du borohydrure de sodium afin d'obtenir un dialcool de formule 12; la réaction des groupes hydroxyle du dialcool avec du chlorure de mésyle afin d'introduire deux groupes de méthane sulfonyle et former un composé dimésylé avec un di-isopropylamine sous pression, puis avec un hydroxyde de sodium afin d'obtenir une tolterodine de base à partir du brome hydrate et la réaction ultérieure de celle-ci avec un acide (+)- tartarique afin d'obtenir le tartrate de (R)-tolterodine.
PCT/IB2007/003377 2006-07-04 2007-06-29 Procédé de préparation de tartrate de (r)-tolterodine Ceased WO2008020332A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MXPA06007686A MXPA06007686A (es) 2006-07-04 2006-07-04 Proceso para la obtencion del tartrato de tolterodina.
MXPA/A/2006/007686 2006-07-04

Publications (2)

Publication Number Publication Date
WO2008020332A2 true WO2008020332A2 (fr) 2008-02-21
WO2008020332A3 WO2008020332A3 (fr) 2008-05-29

Family

ID=39031182

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2007/003377 Ceased WO2008020332A2 (fr) 2006-07-04 2007-06-29 Procédé de préparation de tartrate de (r)-tolterodine

Country Status (3)

Country Link
ES (1) ES2291135B1 (fr)
MX (1) MXPA06007686A (fr)
WO (1) WO2008020332A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010078703A1 (fr) * 2008-12-29 2010-07-15 药源药物化学（上海）有限公司 Procédé de préparation de toltérodine et son l-tartrate
WO2010046801A3 (fr) * 2008-10-21 2011-04-21 Alembic Limited Procédé de préparation de tartrate de tolterodine
EP2476665A1 (fr) 2011-01-17 2012-07-18 Cambrex Profarmaco Milano S.r.l. Procédé pour la préparation de N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)- 3-phenyl propylamine et ses sels démarrant à partir d'un nouvel intermédiaire
WO2012098044A1 (fr) 2011-01-17 2012-07-26 Cambrex Profarmaco Milano S.R.L. Procédé pour la préparation de n,n-diisopropyl-3-(2-hydroxy-5-méthylphényl)-3-phénylpropylamine et de ses sels à partir d'un nouvel intermédiaire

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN191835B (fr) * 2001-08-03 2004-01-10 Ranbaxy Lab Ltd
CZ293791B6 (cs) * 2003-06-05 2004-07-14 Zentiva, A.S. Způsob výroby N,N-diisopropyl-3-(2-hydroxy-5-methylfenyl)-3-fenylpropylaminu v jeho racemické nebo opticky aktivní formě
ITMI20041920A1 (it) * 2004-10-11 2005-01-11 Chemi Spa Processo per la preparazione di n, n-diisopropil-3-2-idrossi-5-metilfenil-3-fenil-propabammina
US7355077B2 (en) * 2004-10-28 2008-04-08 Dr. Reddy's Laboratories Limited Process for preparing tolterodine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010046801A3 (fr) * 2008-10-21 2011-04-21 Alembic Limited Procédé de préparation de tartrate de tolterodine
WO2010078703A1 (fr) * 2008-12-29 2010-07-15 药源药物化学（上海）有限公司 Procédé de préparation de toltérodine et son l-tartrate
EP2476665A1 (fr) 2011-01-17 2012-07-18 Cambrex Profarmaco Milano S.r.l. Procédé pour la préparation de N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)- 3-phenyl propylamine et ses sels démarrant à partir d'un nouvel intermédiaire
WO2012098044A1 (fr) 2011-01-17 2012-07-26 Cambrex Profarmaco Milano S.R.L. Procédé pour la préparation de n,n-diisopropyl-3-(2-hydroxy-5-méthylphényl)-3-phénylpropylamine et de ses sels à partir d'un nouvel intermédiaire

Also Published As

Publication number Publication date
WO2008020332A3 (fr) 2008-05-29
ES2291135A1 (es) 2008-02-16
MXPA06007686A (es) 2008-01-07
ES2291135B1 (es) 2008-12-16

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